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The T-cell leukemia-associated ribosomal RPL10 R98S mutation enhances JAK-STAT signaling

Lookup NU author(s): Claire Schwab, Professor Christine Harrison

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Abstract

© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. Several somatic ribosome defects have recently been discovered in cancer, yet their oncogenic mechanisms remain poorly understood. Here we investigated the pathogenic role of the recurrent R98S mutation in ribosomal protein L10 (RPL10 R98S) found in T-cell acute lymphoblastic leukemia (T-ALL). The JAK-STAT signaling pathway is a critical controller of cellular proliferation and survival. A proteome screen revealed overexpression of several Jak-Stat signaling proteins in engineered RPL10 R98S mouse lymphoid cells, which we confirmed in hematopoietic cells from transgenic Rpl10 R98S mice and T-ALL xenograft samples. RPL10 R98S expressing cells displayed JAK-STAT pathway hyper-activation upon cytokine stimulation, as well as increased sensitivity to clinically used JAK-STAT inhibitors like pimozide. A mutually exclusive mutation pattern between RPL10 R98S and JAK-STAT mutations in T-ALL patients further suggests that RPL10 R98S functionally mimics JAK-STAT activation. Mechanistically, besides transcriptional changes, RPL10 R98S caused reduction of apparent programmed ribosomal frameshifting at several ribosomal frameshift signals in mouse and human Jak-Stat genes, as well as decreased Jak1 degradation. Of further medical interest, RPL10 R98S cells showed reduced proteasome activity and enhanced sensitivity to clinical proteasome inhibitors. Collectively, we describe modulation of the JAK-STAT cascade as a novel cancer-promoting activity of a ribosomal mutation, and expand the relevance of this cascade in leukemia.


Publication metadata

Author(s): Girardi T, Vereecke S, Sulima SO, Khan Y, Fancello L, Briggs JW, Schwab C, De Beeck JO, Verbeeck J, Royaert J, Geerdens E, Vicente C, Bornschein S, Harrison CJ, Meijerink JP, Cools J, Dinman JD, Kampen KR, De Keersmaecker K

Publication type: Article

Publication status: Published

Journal: Leukemia

Year: 2018

Volume: 32

Issue: 3

Pages: 809-819

Print publication date: 01/03/2018

Online publication date: 24/07/2017

Acceptance date: 04/07/2017

ISSN (print): 0887-6924

ISSN (electronic): 1476-5551

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/leu.2017.225

DOI: 10.1038/leu.2017.225


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